Dual efficacy of tocilizumab in managing PD-1 inhibitors-induced myocardial inflammatory injury and suppressing tumor growth with PD-1 inhibitors: a preclinical study.

Abstract

The combined use of tocilizumab (TCZ) and immune checkpoint inhibitors (ICIs) in cancer treatment is gaining attention, but preclinical studies are lacking. Our study aims to investigate the synergistic anti-tumor effect of TCZ combined with ICIs and its role in treating immune-related adverse events (irAEs). The clinical significance of high interleukin-6 (IL-6) expression in tumor patients was analyzed from the Cancer Genome Atlas (TCGA) database. The expression levels of IL-6 were compared before and during the onset of ICIs-associated myocarditis patients. ICIs-related myocardial inflammatory injury and therapeutic lung cancer models were constructed in C57BL/6 J mice using murine-derived programmed death-1 (PD-1) inhibitors alone or in combination with TCZ. Possible inflammatory mechanisms were proposed and validated. The anti-tumor effects and mechanisms of both drugs in combination were assessed. Patients with high IL-6 expression had a poor prognosis, and those with ICIs-associated myocarditis exhibited elevated IL-6 from baseline. In the PD-1 inhibitors-associated myocardial inflammatory injury mouse model, the levels of IL-6 in the blood and cardiac tissues were significantly elevated. TCZ ameliorated immune myocardial inflammatory injury by inhibiting the IL-6/janus kinase 2 (JAK2)/signal transducer and activator of the transcription 3 (STAT3) pathway. The group treated with PD-1 inhibitors combined with TCZ showed significantly slower tumor growth than that treated with PD-1 inhibitors alone. TCZ resisted tumor growth by inhibiting the IL-6-JAK2-STAT3 pathway. By targeting the IL-6-JAK2-STAT3 pathway, TCZ can alleviate PD-1 inhibitors-associated myocardial inflammatory injury mediated by M1-polarized macrophages and plays a synergistic anti-tumor role by inhibiting lung cancer cell proliferation.